Journal of Korean Medical Science

  • 제33권53호
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  • Pages.298.1-298.10
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  • 2018
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  • 1011-8934(pISSN)
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  • 1598-6357(eISSN)
대한의학회 (Korean Acad Medical Sciences)
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Assessment of Hepatic Cytochrome P450 3A Activity Using Metabolic Markers in Patients with Renal Impairment

  • Kim, Andrew HyoungJin (Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Yoon, Sumin (Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Lee, Yujin (Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Lee, Jieon (Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Bae, Eunjin (Department of Internal Medicine, Gyeongsang National University Changwon Hospital) ;
  • Lee, Hajeong (Department of Internal Medicine, Seoul National University College of Medicine and Hospital) ;
  • Kim, Dong Ki (Department of Internal Medicine, Seoul National University College of Medicine and Hospital) ;
  • Lee, SeungHwan (Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Yu, Kyung-sang (Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Jang, In-Jin (Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital) ;
  • Cho, Joo-Youn (Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital)
  • 투고 : 2018.07.25
  • 심사 : 2018.10.14
  • 발행 : 2018.12.31
⟨ 이전 논문 다음 논문 ⟩

초록

Background: The renal function of individuals is one of the reasons for the variations in therapeutic response to various drugs. Patients with renal impairment are often exposed to drug toxicity, even with drugs that are usually eliminated by hepatic metabolism. Previous study has reported an increased plasma concentration of indoxyl sulfate and decreased plasma concentration of $4{\beta}$-hydroxy (OH)-cholesterol in stable kidney transplant recipients, implicating indoxyl sulfate as a cytochrome P450 (CYP) inhibiting factor. In this study, we aimed to evaluate the impact of renal impairment severity-dependent accumulation of indoxyl sulfate on hepatic CYP3A activity using metabolic markers. Methods: Sixty-six subjects were enrolled in this study; based on estimated glomerular filtration rate (eGFR), they were classified as having mild, moderate, or severe renal impairment. The plasma concentration of indoxyl sulfate was quantified using liquid chromatography-mass spectrometry (LC-MS). Urinary and plasma markers ($6{\beta}$-OH-cortisol/cortisol, $6{\beta}$-OH-cortisone/cortisone, $4{\beta}$-OH-cholesterol) for hepatic CYP3A activity were quantified using gas chromatography-mass spectrometry (GC-MS). The total plasma concentration of cholesterol was measured using the enzymatic colorimetric assay to calculate the $4{\beta}$-OH-cholesterol/cholesterol ratio. The correlation between variables was assessed using Pearson's correlation test. Results: There was a significant negative correlation between MDRD eGFR and indoxyl sulfate levels. The levels of urinary $6{\beta}$-OH-cortisol/cortisol and $6{\beta}$-OH-cortisone/cortisone as well as plasma $4{\beta}$-OH-cholesterol and $4{\beta}$-OH-cholesterol/cholesterol were not correlated with MDRD eGFR and the plasma concentration of indoxyl sulfate. Conclusion: Hepatic CYP3A activity may not be affected by renal impairment-induced accumulation of plasma indoxyl sulfate.

키워드

과제정보

연구 과제 주관 기관 : National Research Foundation of Korea

참고문헌

  1. Dixon J, Lane K, Macphee I, Philips B. Xenobiotic metabolism: the effect of acute kidney injury on non-renal drug clearance and hepatic drug metabolism. Int J Mol Sci 2014;15(2):2538-53. https://doi.org/10.3390/ijms15022538
  2. Philips BJ, Lane K, Dixon J, Macphee I. The effects of acute renal failure on drug metabolism. Expert Opin Drug Metab Toxicol 2014;10(1):11-23. https://doi.org/10.1517/17425255.2013.835802
  3. Vanholder R, Schepers E, Pletinck A, Nagler EV, Glorieux G. The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J Am Soc Nephrol 2014;25(9):1897-907. https://doi.org/10.1681/ASN.2013101062
  4. Suzuki Y, Itoh H, Fujioka T, Sato F, Kawasaki K, Sato Y, et al. Association of plasma concentration of $4{\beta}$-hydroxycholesterol with CYP3A5 polymorphism and plasma concentration of indoxyl sulfate in stable kidney transplant recipients. Drug Metab Dispos 2014;42(1):105-10. https://doi.org/10.1124/dmd.113.054171
  5. Hanada K, Ogawa R, Son K, Sasaki Y, Kikkawa A, Ichihara S, et al. Effects of indoxylsulfate on the in vitro hepatic metabolism of various compounds using human liver microsomes and hepatocytes. Nephron, Physiol 2006;103(4):179-86. https://doi.org/10.1159/000092919
  6. Nishimura M, Yaguti H, Yoshitsugu H, Naito S, Satoh T. Tissue distribution of mRNA expression of human cytochrome P450 isoforms assessed by high-sensitivity real-time reverse transcription PCR. Yakugaku Zasshi 2003;123(5):369-75. https://doi.org/10.1248/yakushi.123.369
  7. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013;138(1):103-41. https://doi.org/10.1016/j.pharmthera.2012.12.007
  8. Knights KM, Rowland A, Miners JO. Renal drug metabolism in humans: the potential for drug-endobiotic interactions involving cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Br J Clin Pharmacol 2013;76(4):587-602. https://doi.org/10.1111/bcp.12086
  9. Michaud J, Nolin TD, Naud J, Dani M, Lafrance JP, Leblond FA, et al. Effect of hemodialysis on hepatic cytochrome P450 functional expression. J Pharmacol Sci 2008;108(2):157-63. https://doi.org/10.1254/jphs.08042FP
  10. Oh J, Kim AH, Lee S, Cho H, Kim YS, Bahng MY, et al. Effects of renal impairment on the pharmacokinetics and pharmacodynamics of a novel dipeptidyl peptidase-4 inhibitor, evogliptin (DA-1229). Diabetes Obes Metab 2017;19(2):294-8. https://doi.org/10.1111/dom.12813
  11. Yeung CK, Shen DD, Thummel KE, Himmelfarb J. Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport. Kidney Int 2014;85(3):522-8. https://doi.org/10.1038/ki.2013.399
  12. Doogue MP, Polasek TM. Drug dosing in renal disease. Clin Biochem Rev 2011;32(2):69-73.
  13. Monteiro MS, Carvalho M, Bastos ML, Guedes de Pinho P. Metabolomics analysis for biomarker discovery: advances and challenges. Curr Med Chem 2013;20(2):257-71. https://doi.org/10.2174/092986713804806621
  14. Watanabe M, Kumai T, Matsumoto N, Tanaka M, Suzuki S, Satoh T, et al. Expression of CYP3A4 mRNA is correlated with CYP3A4 protein level and metabolic activity in human liver. J Pharmacol Sci 2004;94(4):459-62. https://doi.org/10.1254/jphs.94.459
  15. Liu CH, Peck K, Huang JD, Lin MS, Wang CH, Hsu WP, et al. Screening CYP3A single nucleotide polymorphisms in a Han Chinese population with a genotyping chip. Pharmacogenomics 2005;6(7):731-47. https://doi.org/10.2217/14622416.6.7.731
  16. Shin KH, Choi MH, Lim KS, Yu KS, Jang IJ, Cho JY. Evaluation of endogenous metabolic markers of hepatic CYP3A activity using metabolic profiling and midazolam clearance. Clin Pharmacol Ther 2013;94(5):601-9. https://doi.org/10.1038/clpt.2013.128
  17. Kim B, Moon JY, Choi MH, Yang HH, Lee S, Lim KS, et al. Global metabolomics and targeted steroid profiling reveal that rifampin, a strong human PXR activator, alters endogenous urinary steroid markers. J Proteome Res 2013;12(3):1359-68. https://doi.org/10.1021/pr301021p
  18. Lee J, Kim AH, Yi S, Lee S, Yoon SH, Yu KS, et al. Distribution of exogenous and endogenous CYP3A markers and related factors in healthy males and females. AAPS J 2017;19(4):1196-204. https://doi.org/10.1208/s12248-017-0090-8
  19. Moon JY, Kang SM, Lee J, Cho JY, Moon MH, Jang IJ, et al. GC-MS-based quantitative signatures of cytochrome P450-mediated steroid oxidation induced by rifampicin. Ther Drug Monit 2013;35(4):473-84. https://doi.org/10.1097/FTD.0b013e318286ee02
  20. de Graan AJ, Sparreboom A, de Bruijn P, de Jonge E, van der Holt B, Wiemer EA, et al. $4{\beta}$-Hydroxycholesterol as an endogenous CYP3A marker in cancer patients treated with taxanes. Br J Clin Pharmacol 2015;80(3):560-8. https://doi.org/10.1111/bcp.12707
  21. Bodin K, Andersson U, Rystedt E, Ellis E, Norlin M, Pikuleva I, et al. Metabolism of 4 beta-hydroxycholesterol in humans. J Biol Chem 2002;277(35):31534-40. https://doi.org/10.1074/jbc.M201712200
  22. Diczfalusy U, Nylen H, Elander P, Bertilsson L. $4{\beta}$-Hydroxycholesterol, an endogenous marker of CYP3A4/5 activity in humans. Br J Clin Pharmacol 2011;71(2):183-9. https://doi.org/10.1111/j.1365-2125.2010.03773.x
  23. Marde Arrhen Y, Nylen H, Lovgren-Sandblom A, Kanebratt KP, Wide K, Diczfalusy U. A comparison of $4{\beta}$-hydroxycholesterol : cholesterol and $6{\beta}$-hydroxycortisol: cortisol as markers of CYP3A4 induction. Br J Clin Pharmacol 2013;75(6):1536-40. https://doi.org/10.1111/bcp.12016
  24. Diczfalusy U, Kanebratt KP, Bredberg E, Andersson TB, Bottiger Y, Bertilsson L. 4beta-hydroxycholesterol as an endogenous marker for CYP3A4/5 activity. Stability and half-life of elimination after induction with rifampicin. Br J Clin Pharmacol 2009;67(1):38-43. https://doi.org/10.1111/j.1365-2125.2008.03309.x
  25. Furuta T, Suzuki A, Mori C, Shibasaki H, Yokokawa A, Kasuya Y. Evidence for the validity of cortisol 6 beta-hydroxylation clearance as a new index for in vivo cytochrome P450 3A phenotyping in humans. Drug Metab Dispos 2003;31(11):1283-7. https://doi.org/10.1124/dmd.31.11.1283
  26. Chan KC, Lit LC, Law EL, Tai MH, Yung CU, Chan MH, et al. Diminished urinary free cortisol excretion in patients with moderate and severe renal impairment. Clin Chem 2004;50(4):757-9. https://doi.org/10.1373/clinchem.2003.029934
  27. Kim AH, Kim B, Rhee SJ, Lee Y, Park JS, Lee SM, et al. Assessment of induced CYP3A activity in pregnant women using $4{\beta}$-hydroxycholesterol: cholesterol ratio as an appropriate metabolic marker. Drug Metab Pharmacokinet 2018;33(3):173-8. https://doi.org/10.1016/j.dmpk.2018.04.004

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